ABSTRACT Most chemotherapeutic agents are proliferation dependent in their mechanisms of action and are active against rapidly dividing cells. This is a challenge because prostate cancer is clinically slow growing. In addition, prostate cancer is heterogeneous and the drugs currently in use do not kill all populations of tumor cells leading to relapse and regeneration of the tumor. Resistance to docetaxel is another great challenge with chemotherapy of prostate cancer. Brusatol is a protein synthesis inhibitor in cells and it has specific inhibitory activity on nuclear factor erythroid 2-related factor 2 (Nrf2). Because it inhibits protein synthesis, it can kill all tumor cells regardless of heterogeneity. As a result of its non-selective mechanism of action, and other challenges to its clinical translation, the active targeting or site-specific delivery of brusatol to tumors is essential. In addition, the effect of brusatol on Nrf2 is short-lived. The sustained release of brusatol from a delivery system can ensure a prolonged effect on Nrf2 similar to repeated dosing. In addition to its cytotoxic effects, brusatol can also prevent the development of drug resistance and reverse the resistance to other drugs. The innovation and advantages of these approach are numerous. The nanoparticle platform is essential: (a) to prevent or reduce toxicity to healthy cells (the drugs will be released in the tumor microenvironment as a result of the EPR effect and active targeting by binding to PSMA), (b) for sustained drug release and thereby reverse the short-lived effect on Nrf2, (c) to increase drug concentration in the tumor and thereby increase therapeutic efficacy. In addition, combination therapy of brusatol and docetaxel in a nanoparticle platform allows targeting multiple pathways with the resultant improvement in therapeutic efficacy. Furthermore, combination of both drugs can prevent and/or reverse resistance to docetaxel by well- known reported mechanisms. This can solve the problem of docetaxel resistance. Finally, the brusatol- and docetaxel-loaded nanoparticles as a result of accumulation within the tumor microenvironment can augment and improve the efficacy of radiotherapy. Docetaxel, in addition to its cytotoxicity greatly increases the ROS levels while brusatol inhibits the antioxidant response. This effects greatly increase ROS levels specifically within the tumor. Since radiotherapy exerts its effects by increasing ROS and causing DNA strand breaks, the nanoparticle platform holds the promise to significantly augment radiotherapy within the tumor microenvironment. Our hypothesis is that the fabrication of stealth, targeted, brusatol- and docetaxel-loaded nanoparticles will reverse the transient brusatol effect on Nrf2 by sustained, continuous release from nanoparticles. Nanoparticle combination therapy will: (1) suppress and/or reverse chemoresistance to docetaxel (2) reduce adverse effects, and (3) increase therapeutic efficacy as a result of affecting multiple proliferation pathways of cancer cells and site-specific delivery. To achieve the goals of the proposal, we have the following aims: (1) Fabrication, characterization and optimization of stealth, targeted brusatol- and docetaxel-loaded nanoparticles and controls. (2) Cytotoxicity and cellular internalization studies, flow cytometry analyses and other in vitro studies will be carried done using fluorescent dye- and drug-loaded nanoparticles. (3) Biodistribution, maximum tolerable dose (MTD) and efficacy studies will be done in mice.